Schizophrenia affects approximately 5 million people. At present, the most widespread treatments for schizophrenia are the ‘atypical’ antipsychotics, which combine dopamine (D2) receptor antagonism with serotonin (5-HT2A) receptor antagonism. Despite the reported advances in efficacy and side-effect liability of atypical antipsychotics over typical antipsychotics, these compounds do not adequately treat all of the symptoms of schizophrenia and are accompanied by problematic side effects including weight gain (Allison, D. B., et. al., Am. J. Psychiatry, 156: 1686–1696, 1999; Masand, P. S., Exp. Opin. Pharmacother. I: 377–389, 2000; Whitaker, R., Spectrum Life Sciences. Decision Resources. 2:1–9, 2000). Novel antipsychotics which are effective in treating the mood disorders or the cognitive impairments in schizophrenia without producing weight gain would represent a significant advance in the treatment of schizophrenia.
5-HT2C agonists and partial agonists represent a novel therapeutic approach toward the treatment of schizophrenia. Several lines of evidence support a role for 5-HT2C receptor agonism as a treatment for schizophrenia. Studies with 5-HT2C antagonists suggest that these compounds increase synaptic levels of dopamine and may be effective in animal models of Parkinson's disease (Di Matteo, V., et. al., Neuropharmacology 37: 265–272, 1998; Fox, S. H., et. al., Experimental Neurology 151: 35–49, 1998). Since the positive symptoms of schizophrenia are associated with increased levels of dopamine, compounds with actions opposite those of 5-HT2C antagonists such as 5-HT2C agonists and partial agonists should reduce levels of synaptic dopamine. Recent studies have demonstrated that 5-HT2C agonists decrease levels of dopamine in the prefrontal cortex and nucleus accumbens (Millan, M. J., et. al., Neuropharmacology 37: 953–955, 1998; Di Matteo, V., et. al., Neuropharmacology 38: 1195–1205, 1999; Di Giovanni, G., et. al., Synapse 35: 53–61, 2000), brain regions that are thought to mediate critical antipsychotic effects of drugs like clozapine. In contrast, 5-HT2C agonists do not decrease dopamine levels in the striatum, the brain region most closely associated with extrapyramidal side effects. In addition, a recent study demonstrates that 5-HT2C agonists decrease firing in the ventral tegmental area (VTA), but not in substantia nigra. The differential effects of 5-HT2C agonists in the mesolimbic pathway relative to the nigrostriatal pathway suggests that 5-HT2C agonists will have limbic selectivity and will be less likely to produce extrapyramidal side effects associated with typical antipsychotics.
Atypical antipsychotics bind with high affinity to 5-HT2C receptors and function as 5-HT2C receptor antagonists or inverse agonists. Weight gain is a problematic side effect associated with atypical antipsychotics such as clozapine and olanzapine and it has been suggested that 5-HT2C antagonism is responsible for the increased weight gain. Conversely, stimulation of the 5-HT2C receptor is known to result in decreased food intake and body weight (Walsh et. al., Psychopharmacology 124: 57–73, 1996; Cowen, P. J., et. al., Human Psychopharmacology 10: 385–391, 1995; Rosenzweig-Lipson, S., et. al., ASPET abstract, 2000). As a result, 5-HT2C agonists and partial agonists will be less likely to produce the body weight increases associated with current atypical antipsychotics. Indeed, 5-HT2C agonists and partial agonists are of great interest for the treatment of obesity, a medical disorder characterized by an excess of body fat or adipose tissue and associated with such comorbidities as Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality.